New choline derivative and process for making same



Patented Jan. 10, 1933 UNITED STATES PATENT OFFICE OTTO DAL'MER AND GLAUS DIEHI}, OF DARMSTADT, GERMANY No Drawing. Application filed April 18, 1931,.,Seria1 No. 531,252, andin Germany May 8, 1930.

The present invention relates to the production of a new type of compounds havingtherapeutic properties, viz: carhamic acid esters from compounds of thecholine type. Such 5 substances have hitherto neither been described nor have these been known; so far only compounds have been known in which one hydrogen atom of the NH grouphas been substituted by an aryl group. These substances possess anaesthetic properties, whilst the products of the present invention affect the blood-pressure without having the disagreeable physical properties of other choline compounds. It has been shown that generally speaking these products show the above-mentioned properties. Especially it has been shown that the methochloride of carbamic acid-,B-di-inethyl-aminoeethyhester (trimethyl-, (amino-formyL) -,8-oxy-ethyl] ammonium chloride) is most advantageously applied. The above compounds are prepared by reaction of a substance with aliphatic halogen and a tertiary aliphatic base,

Generally the following solvents have proved as advisable in use: ethyl-alcohol, methyl-alcohol, acetone, chloroform.

.methioclide of carbamic acid-fl-dimethylaniino-ethyl-ester (trimethyl-, [-(aminoc0; formyl-) -fi-oXy-ethyl] ammonium-iodide) is obtained as a snow white crystalline powder which turns slightly yellow in day-light and which has a melting point of 200 C. The substance dissolves readily in water with a neutral reaction. The chloride forms well defined thin crystals melting at 208 C. which are stable to light.

NHz-CO-O OHr-CHz-N 2. 16 grams of carbamic acid ,B-diethylamino-ethyl-ester are boiled for hour under a refluxcondenser with 1,5 grams methyliodide and 50 cc. methyl-alcohol. The reaction product is stirred with ether, filtered off and crystallized several times from absolute alcohol. In this way one obtains the methiodide of carbamic acid-,B-diethylamino-ethylester (diethyl-, methylv (amindformyl B oXy-ethyL] -ammonium-iodide) in beautiful white crystals of melting point 123-124; C. which are easily soluble in water. The yield issatisfactory.

3. 11 grams y chloropropyl urethane (melting point 61) are heated with 5 grams of trimethyl amine in a closed vessel or 7 hours up to 50. The obtained crystals are powdered with acetone, sucked off and dissolved in boiling methanol; acetone is added.

The methochloride of carbamic acid- -dimethylamino-propyl-ester is separated ofi in beautiful water-soluble crystals of a melting point of 207208 C.

CHI

the cooled viscous mass with ether, it becomes crystalline. The crystal cake after separation is again rubbed up with acetone and recrystallized from absolute alcohol. In this way the iodo- (amino-formyl-fl-oxy) -ethylate of carbamic acid-fl-diethyl-amino-ethyl-ester (diethyl-di- (amino-formyL) -}3-oxy-ethyl-] ammonium-iodide) is obtained in good yield and having a melting point of 151 C.

NHz-CO-OCHa-OlIg-CHg-Cl N-CH: NHx-CO-O-OHg-CHr-OHr-N-OH;

4. 7 grams a-methyl-a-ethyl-fl-dimethylamino-carbamic-acid ethylester are heated with 10 cc. methyl-alcohol and 10 g. methyliodide by means of vapour, whereby crystallization takes place. The separated iodinemethylate of a-methyl-a-ethyl-B-dimethylamino-carbamic acid ethylester is re-crystalso: lized from methyl alcohol-acetone and forms a nearly white water and alcohol soluble crystal powder of a melting point of 230.

grams of carbamic acid-B-diethylamino-ct yl-ester are heated for 3 hours in a sealed tube at 50 C. with 17 grams of 'ethylene iodo-hydrine (molecular weight 172). The reaction product, which crystallizes after cooling, is worked up with ether, filtered 011' and re-crystallized several times from absolute alcohol. ,B-oxy-ethyl-iodide of carbamic acid-B-diethylamino ethyl ester (diethyl-, -fl-oXy-ethyl-, [(amino-formyl-)- fl-oxy-ethyL] -ammonium-iodide) is obtained in good yield in white crystals easily soluble iln iwacter, having a melting point of 105- 7. Molecular'wei hts of carbamic acid-#- diethyl-amino-ethy -ester and w-bromo-acetophenone are melted together for a short time. The vitreous melt is rubbed up with acetone, filtered ofi and the product re-crystallized from absolute alcohol. The phenacyl-bromide of carbamic acid-B-drethyl-aminoethyl-ester (diethyl-, phenacyl-, [(aminoformyl- 8.-oxy-ethyl]-ammonium-bromide) forms w ite small needles united intobunches,

which are soluble in water with a neutral reaction and have a melting point of 182 G.

6. 16 amino-ct ams of carbamic acid-B-dieth l- Iy1 l-ester and 21.5 grams of B-iodi eethyl-uret ane molecular Weight 215) dissolved therein. t is then heated for 5 hours in a sealed tube at 90 C. By rubbing up OKs- BOE fl- (4-oxy-phenyl-) -ethylate of carbamic acid- B-dimethyl amino ethyl ester (dimethyl- [/3 S4 oxy phenyl) ethyl]-,[(amino-for myl- -fl-oxy-ethg -ammonium iodide) in white crystals w ic melt at 152-153 C. and

which are easily soluble in water with a neutral reaction.

OH: CHz-CH2-N 9. Molecular quantities of pseudo l-phenyl-,1- (famino-formyL) -oXy-,2-dimethylamino-propane and methyl iodide are heated for a short time in methyl alcohol on the steam bath. The reaction product is rubbed up with ether and recrystallized from absolute a1- cohol. The methiodide of pseudo 1-phenyl-,1- (amino-formyl-) -oxy-,2-dimethylamino-propane melts at 22022l G. and is easily soluble in water.

2. Process for the production of derivatives of the choline type consisting in bringing into chemical combination by means of heating in solution equi-molecular quantities of a saturated aliphatic halogen compound, the halogen of which is of the character and reactivity of the alkyl halides, with a saturated aliphatic tertiary base, the nitrogen atom of the latter being bound to an aliphatic chain, while one hydrogen atom of one alkyl of one of the two mentioned starting materials is substituted by the carbaminoyloxy radical 3. As a new and useful product of therapeutic value the methochloride of carbamic acid-,B-dimethyl-amino-ethyl-ester (trimethyl-, (amino-formyL) -,8-oXy-ethyl] -ammonium-chloride) consisting of snow white crystalline powder which melts at 200 0., being easily soluble in water, therein showing a neutral reaction, having the following formula H OH: NH2-oo-ooH2cH2NcH;

4. Process for the production of derivatives of the choline type consisting in bringing into chemical combination by means of heating one mole of a saturated alkyl halide with one mole of a saturated aliphatic tertiary nitrogenous base, while one hydrogen atom of one alkyl of one of the two mentioned starting materials is substituted by the carbaminoyloxy radical (NHzC=O).

OTTO DALMER. CLAUS DIEHL. 

